Canine Models of Atopic Dermatitis: A Useful Tool with Untapped Potential

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Canine Models of Atopic Dermatitis: A Useful Tool with
Untapped Potential
Rosanna Marsella1 and Giampiero Girolomoni2
Animal models have contributed greatly to the
expansion of knowledge in the field of atopic
dermatitis (AD). Some species, such as the dog,
naturally and commonly develop a pruritic dermatitis
that is clinically and immunologically extremely
similar to human AD. Recently, canine models of AD
have been validated. In one of these models (Beagles),
AD can be reliably reproduced upon allergen chal-
lenge, providing a tool with which to study effectively
how AD is affected by allergen exposure. Interestingly,
decreased epidermal filaggrin expression and dis-
turbed extrusion of lamellar bodies by keratinocytes
are present in these dogs, as well as increased
transepidermal water loss, particularly in sites char-
acteristically affected by AD. Owing to the remarkable
similarity with the human disease, these dog models
not only can help answer questions relative to the
pathogenesis of the disease but also can be used as
tools for rapid screening of drugs with potential
clinical application, including those aimed at restoring
epidermal barrier dysfunction.
Journal of Investigative Dermatology (2009) 129, 2351–2357;
doi:10.1038/jid.2009.98; published online 11 June 2009
INTRODUCTION
Animal models have been instrumental in gaining an insight
into many aspects of the pathogenesis of atopic dermatitis
(AD), from improving our understanding of the immunologi-
cal mechanisms to gaining an appreciation for the impor-
tance of epicutaneous exposure to allergens (Scharschmidt
and Segre, 2008). These models have helped answer many
questions, although many more still remain and newer
questions develop as we continue to unveil the intricacy of
AD. The biggest challenge remains in the development of a
clinically relevant model that could shed light on the
mechanisms behind the distribution of lesions in AD and
the ‘‘atopic march.’’ Although mouse models have many
benefits, including low cost, short time to maturity, avail-
ability of reagents, and the opportunity to evaluate the effects
of specific genetic alterations, they also have significant
limitations in how clinically similar their disease is to
naturally occurring human AD. Thus, it would be beneficial
to use a species that is genetically closer to humans and that
would naturally develop a disease as similar as possible to
human AD.
Dogs are affected with a natural homolog of human AD
(Table 1) (Helton Rhodes et al., 1987; Willemse, 1988). This
disease manifests as a recurrent pruritic dermatitis that is
genetically inherited and is associated, in most but not all
cases, with IgE against environmental allergens (Lian and
Halliwell, 1998; Olivry et al., 2001). It is estimated that
canine AD affects, on average, 10–15% of the canine
population (Hillier and Griffin, 2001a; Williams, 2001), but
it seems that AD, even in dogs, has become increasingly
more common in the past decade. Studies from the early
1970s reported a canine AD prevalence of as low as 3.3%
(Halliwell and Schwatrzman, 1971), whereas a survey in the
late 1980s indicated that AD affects as many as 27% of dogs
in the United States (DeBoer, 1989). Whether this increase is
due to an enhanced awareness of veterinarians, leading to a
more frequent diagnosis, or whether this is a true increase
due to a changed lifestyle of pet dogs is unknown.
Unfortunately, there are no comparative epidemiological
studies on canine and human AD. These studies may provide
important clues to the role of shared environmental factors.
What is known is that, despite the fact that environmental
sensitizations are extremely common in dogs with AD, this
species does not experience the ‘‘atopic march’’ and no
development of asthma occurs, even in individuals with the
most severe dermatitis. Thus, dogs may prove to be key in
understanding what induces or what prevents the develop-
ment of the atopic march. The purpose of this review is to
briefly describe the clinical and immunological features of
canine AD and then to describe a few models of AD in dogs
and the lessons learned from these models.
Canine AD
Canine AD typically develops in young dogs (between 1 and
3 years of age), and it may have seasonal manifestations
initially, with progressive worsening over time. Food aller-
gens can be an important flare factor (Hillier and Griffin,
& 2009 The Society for Investigative Dermatology www.jidonline.org 2351
REVIEW
Received 2 December 2008; revised 24 February 2009; accepted 27 February
2009; published online 11 June 2009
1Department of Small Animal Clinical Sciences, College of Veterinary
Medicine, University of Florida, Gainesville, Florida, USA and 2Section of
Dermatology and Venereology, Department of Biomedical and Surgical
Sciences, University of Verona, Verona, Italy
Correspondence: Dr Rosanna Marsella, Department of Small Animal Clinical
Sciences, College of Veterinary Medicine, University of Florida, Gainesville,
Florida 32610-0126, USA.
E-mail: MarsellaR@vetmed.ufl.edu
Abbreviations: AD, atopic dermatitis; APT, atopy patch test;
TEWL, transepidermal water loss
2001b; Olivry et al., 2007). Therefore, an investigation of
food allergies is indicated in most cases, particularly in
nonseasonal disease or in cases in which AD develops in
particularly young dogs (for example, o6 months old).
Allergic sensitization to environmental allergens is detected
in the vast majority of cases (Hill et al., 2001), although
cases clinically indistinguishable from AD in the absence
of detectable allergen-specific IgE are occasionally seen
(DeBoer, 2004). Whether these dogs could be the canine
homolog of the ‘‘intrinsic’’ or nonallergic AD is currently
unknown. Although allergen-specific IgE is present in most
dogs with AD, clinical disease cannot be predicted by
monitoring IgE levels (DeBoer and Hill, 1999) nor can it be
experimentally induced by simply selecting for the high IgE
trait (Egli et al., 2002). The high IgE trait is inherited as a
dominant trait (de Weck et al., 1997), but the development of
clinical disease is not predicted by the level of IgE. Thus,
although the predisposition toward AD is genetically
inherited (Shaw et al., 2004), such predisposition is most
likely polygenetic and not linked to one single gene.
Interestingly, total IgE levels are not significantly different
between normal and atopic dogs (Hill et al., 1995), and it has
been suggested that this lack of difference may be attributable
to the fact that dogs have very high levels of IgE as compared
with humans, possibly due to parasite exposure. In dogs,
there is an abundance of clinical evidence implying that AD
is antigen driven, and recent studies suggest that there may be
a role for IgE not only in the effector pathway but also in
antigen capture (Olivry et al., 1996; Marsella et al.,
2006a, b, c)
Epidermal barrier defects have been speculated to be
present in dogs with naturally occurring disease. This is
indicated in morphological studies by means of ruthenium
tetroxide electron microscopy showing discontinuity of lipid
lamellae in atopic dogs when compared with normal
controls, even in nonlesional skin (Inman et al., 2001). In
veterinary medicine, it is also speculated that a primary
abnormality in the skin barrier is responsible for the increased
risk of allergic sensitization, which would then lead to
additional cycles of worsening of skin barrier function and
new sensitizations. This hypothesis is based on the distribu-
tion of the lesions (involving contact areas), the various
studies suggesting an impaired skin barrier function, and the
importance of the epicutaneous route of allergen exposure for
both sensitization and induction of flare-ups.
Clinically, canine AD is very similar to its human
counterpart in both the type and the distribution of lesions.Early lesions consist of erythematous macules, generalized
erythema, small vesicles, and oozing in early phases
(Figure 1a). Dogs with AD have increased staphylococcal
colonization and are prone to recurrent bacterial and yeast
infections (Malassezia dermatitis) (DeBoer and Marsella,
2001; Griffin and DeBoer, 2001), which can significantly
contribute to the intensity of the pruritus. With chronicity and
the development of infections, lichenification, hyperpigmen-
tation (Figure 1b), and papular dermatitis ensue. Self-trauma
leads to excoriations and ulcerations, which perpetuate
secondary infections. Classically, extremities of both thoracic
and pelvic limbs are affected (both interdigitally and on the
palmar and plantar surfaces). Pinnae, periocular areas, and
perioral regions are also frequently lesional (Figure 1c and d).
Flexural surfaces of the elbows and knees are also typically
involved in conjunction with the axillary and inguinal area
(Figure 1e and f). Face rubbing, ear scratching, and trauma on
extremities are the first signs noticed, even in the absence of
obvious cutaneous lesions. As the disease progresses,
cutaneous lesions become more evident and pruritus
increases in severity. In some individuals, allergic rhinitis
and conjunctivitis may be observed in conjunction with the
flare-ups of AD, although these are not common manifesta-
tions of atopic disease in dogs.
The similarity between canine and human AD is not
limited to clinical signs. Histologically, lesions are character-
ized by spongiotic dermatitis (Figure 2), with a mononuclear
infiltrate, accumulation of epidermal and dermal
IgEþCD1cþ cells, and epidermal eosinophil microaggre-
gates (Hill et al., 2001; Olivry et al., 1997; Olivry and Hill,
2001), which are consistent with the importance of epidermal
allergen contact. Epitheliotropic cells include Langerhans
cells, T lymphocytes, and rare eosinophils. Dermal cells
comprise mast cells, dermal antigen-presenting cells,
T lymphocytes, and, occasionally, intact and degranulated
eosinophils. Chronic lesions show acanthosis with a scant
inflammatory infiltrate.
Table 1. Similarities between canine and human AD
Canine AD Human AD
Prevalence in the general
population (%)
10–15 5–20 of children
Genetically inherited + +
Age of onset (years) 1–3 o1–5
Skin areas affected Face, skin folds Face, skin folds
Spongiotic dermatitis + +
Skin-infiltrating eosinophils + ±
Skin infiltration by IgE+CD1c+
dendritic cells
+ +
Pruritus Severe Severe
Skin xerosis + +
Increased TEWL + +
Decreased epidermal filaggrin + +
Higher skin colonization by
Staphylococcus aureus
+ +
Th2-dominated immune
responses
+ +
APT + +
IgE-specific responses (%) 80 55–90
Rhinitis and conjunctivitis (%) o5 35
Asthma (%) o5 30
Atopic march No Yes
AD, atopic dermatitis; APT, atopy patch test; TEWL, transepidermal
water loss.
2352 Journal of Investigative Dermatology (2009), Volume 129
R Marsella and G Girolomoni
Canine Models of Atopic Dermatitis
Immunologically, the skin of dogs with naturally occurring
AD shows a T helper 2 (Th2)-polarized response (Olivry
et al., 1999) and a reduced transcription of transforming
growth factor-b compared with controls (Nuttall et al., 2002).
In addition, significantly higher levels of IFN-g, tumor
necrosis factor-a, and IL-2 mRNA were also seen in lesional
skin compared with nonlesional and healthy skin. Thus, it
is hypothesized that canine AD may be associated with
overproduction of IL-4 and that tolerance in healthy
individuals may be related to higher levels of transforming
growth factor-b. Peripheral blood mononuclear cells of dogs
with AD also show a Th2 cytokine pattern compared with
healthy controls (Hayashiya et al., 2002). The average IL-5
mRNA expression in atopic dogs was significantly higher
than that in the control group, and levels of IL-4 mRNA
tended to be higher in the atopic dogs as well. The IFN-g
mRNA expression level in atopic dogs was significantly lower
than in control dogs, but the expression of IL-10 did not differ
between the groups. When chemokines and chemokine
receptors in canine AD were evaluated in dogs with AD, it
was found that thymus- and activation-regulated chemokine
mRNA (Maeda et al., 2002a) and the gene encoding CCR4
(Maeda et al., 2002b) are selectively expressed in the lesional
skin of atopic dogs, but not in the nonlesional atopic skin.
Thus, it is hypothesized that thymus- and activation-regulated
chemokine plays an important role in the recruitment of Th2
lymphocytes in the lesional skin.
The treatment of choice for canine AD is aqueous
immunotherapy, which seems to be 60–85% effective in
controlling clinical signs in cases with nonseasonal disease
(Griffin and Hillier, 2001). Immunotherapy is tailored to the
individual case and uses allergens that are administered by a
subcutaneous injection. Sublingual immunotherapy is still
in its infancy in veterinary medicine, although there is
considerable interest in investigating its efficacy and deter-
mining the best protocols. Other palliative treatments for
canine AD traditionally involve the use of glucocorticoids
and calcineurin inhibitors, both topically and systemically.
Oral cyclosporine has been shown to be as effective as
glucocorticoids (Steffan et al., 2006) and is reserved for cases
that have failed other forms of therapy; topical tacrolimus is
very effective in individuals with localized disease (Marsella
et al., 2004).
It is difficult to discriminate between primary abnormal-
ities and secondary changes when studying AD in dogs with
naturally occurring disease, an important consideration in
their use as a model for human AD. Challenges in this type of
study include difficulties in controlling confounding factors
such as variations in the environment, diet, genetics, and age
of individual lesions. Thus, the identification of a model in
which lesions can be induced consistently and followed over
time to separate primary factors from secondary changes is
important. In an ideal model, the lesions would be induced
with a method of challenge that closely mimics real life so
that the changes observed are reflective of the spontaneous
disease.
Figure 1. Clinical, histological and ultrastructural features of canine AD. In dogs (Beagles) is clinically remarkably similar to human AD in both type of lesions
(acute, erythematous, and exudative lesions (a); and chronic, hyperkeratotic, lichenified lesions (b)) and skin areas involved (facial (c), perioral (d), antebrachial
area (e), axilla (f)).
Figure 2. Histology of recent AD lesion shows typical spongiotic dermatitis.
H&E, bar¼ 50 mm. Reprinted with permission from Marsella et al. (2006a).
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R Marsella and G Girolomoni
Canine Models of Atopic Dermatitis
Role of allergen exposure in canine models
Despite the fact that researchers have worked on canine
models for decades and have attempted to induce disease
using various protocols (Marsella and Olivry, 2003), only
recently have models been identified in which cutaneous
disease can be induced by simple repetitive epicutaneous
exposure to an allergen of choice (Pucheu-Haston et al.,
2008). In such models, AD lesions can be induced with a
simple environmental challenge with house dust mites, and
no tape stripping or injection is needed to induce sensitiza-
tion (Marsella et al., 2006a, b, c). In one model using dogs
genetically selected to express the high IgE trait, a simple
repetitive epicutaneous exposure to Dermatophagoides
farinae leads to sensitization. Allergic sensitization is
monitored by the development of allergen-specific IgE on
both intradermal skin testing and serology testing and by the
development of a pruritic dermatitis that is clinically,
histologically, and immunologically similar to naturally
occurring AD (Marsella et al.,2006a, b, c). In this model,
the severity of dermatitis induced is dose and time
dependent, and the method of challenge consists of environ-
mental exposure to D. farinae. More specifically, a D. farinae
solution is applied to the floor of travel kennels, and the dogs
are free to spend time in the kennels for 3 hours day�1, for
3 days in a row. Thus, with this type of challenge, the allergen
exposure is a combination of epicutaneous, oral, and
inhalatory exposure. The concentration of house dust mites
was selected to mimic the average content of an older
mattress. Typically with this protocol, the dogs start devel-
oping erythema by 6 hours after exposure and symptoms are
quite severe by 96 hours. These dogs are otherwise kept in a
house dust mite–free environment with no access to the
outdoors in order to minimize allergic sensitizations to other
allergens. When the dogs are kept in these conditions and
bathed frequently, only mild AD symptoms occur. The
environmental method of challenge was validated using dogs
with naturally occurring AD hypersensitive to D. farinae and
normal pets that have exposure to an indoor environment but
are not allergic to dust mites (Marsella et al., 2006a, b, c). This
method of challenge was able to induce flare-up of AD in
dogs with naturally occurring disease and no response in
clinically normal dogs, thus ruling out the possibility of an
irritant reaction and ensuring that the method of challenge
would hold true when used in dogs with natural disease.
Clinical lesions consisted of erythematous pruritic papules
and macules in contact areas such as the face, ears, ventral
abdomen, groin, axillae, and feet.
Biopsies of representative lesions in Beagles with high IgE
were taken for histopathology and immunohistochemistry.
There was superficial perivascular dermatitis with mono-
nuclear infiltrates and spongiosis. Lymphocytes and eosino-
phils accumulated in small epidermal microabscesses, with
hyperplasia of epidermal IgE-bearing dendritic cells and an
accumulation of CD1Cþ cells in the superficial dermis
(Figure 3). These findings suggested that this colony of high-
IgE Beagles develops a dermatitis that clinically, histopatho-
logically, and immunologically resembles the naturally
occurring canine disease.
In another group of experimentally sensitized Beagles, an
atopy patch test (APT) with D. farinae showed positive
macroscopic reactions consisting of erythema, edema, and
induration. Positive reactions occurred between 24 and
96 hours after allergen application (Marsella et al., 2005).
Skin biopsies carried out at 4, 24, 48, and 96 hours after
starting allergenic challenge showed that positive APT
reactions are associated with epidermal hyperplasia, in-
creased numbers of Langerhans cells and eosinophils, and
lymphocyte epidermotropism (Olivry et al., 2006). Dermal
inflammation was typically mixed and arranged in a super-
ficial perivascular to interstitial pattern. Numerous IgEþ
CD1cþ dendritic cells and g–d T lymphocytes were also
present. Macroscopically and microscopically, APT reactions
in these experimentally sensitized animals resembled those
seen in lesional biopsy specimens of dogs and humans with
spontaneous AD. Therefore, APT in hypersensitive dogs
provides a relevant experimental model for investigating the
pathogenesis and treatment of both canine and human AD
skin lesions.
In another study evaluating APT, the progressive epider-
mal spongiosis, hyperplasia, and pustulation over the 96-hour
period after allergen application was confirmed in conjunc-
tion with a progressive accumulation of CD1cþ epidermal
Langerhans cells with cluster formation and dermal dendritic
cell infiltration starting at 6 hours (Marsella et al., 2006a, b, c).
Cutaneous infiltration of CD3þ T lymphocytes with epider-
mal clusters was also observed over time. In the same study,
cytokine kinetics of APT reactions was investigated by real-
time reverse transcriptase-PCR before and after 6, 24, 48, and
98 hours of APT. The mRNA expression for the cytokines
IFN-g, IL-6, IL-12p35, IL-13, and IL-18, and that for the
thymus- and activation-regulated chemokine, exhibited
significant increases during the allergen challenge compared
with that at baseline. Cytokines whose mRNA did not show
any appreciable alteration in expression included tumor
necrosis factor-a, IL-12p40, IL-10, RANTES (regulated on
activation normal T-cell expressed and secreted), IL-5, IL-2,
IL-4, and IL-8. No correlation was detected between clinical
scores of the APT sites and cytokines. It was concluded that
IL-6 plays a role in early reactions followed by an increase in
thymus- and activation-regulated chemokine and IL-13
Figure 3. Numerous CD11cþ dendritic cells accumulating in the skin of
sensitized Beagles exposed epicutaneously to D. farinae. Bar¼20 mm.
Reprinted with permission from Marsella et al. (2006c).
2354 Journal of Investigative Dermatology (2009), Volume 129
R Marsella and G Girolomoni
Canine Models of Atopic Dermatitis
mRNA levels, whereas IL-18 progressively increases in later
reactions.
The kinetics of cytokine expression was evaluated in
whole blood from the same Beagles upon environmental
allergen exposure (Maeda et al., 2007). Multiple comparisons
used to detect significant differences in clinical scores and
expression levels of cytokine mRNA showed that the clinical
scores on days 2 and 4 were significantly higher than those
on days 0 and 17, but there were no temporal differences in
the expression levels of IL-4 and IL-13 mRNA. Expression of
transforming growth factor-b mRNA was, however, signifi-
cantly lower on day 4, and the expression of IL-10 mRNA on
days 4 and 17 was significantly lower than on days 0 and 2.
The results indicated that allergen challenge decreases
mRNA expression of regulatory cytokines in whole blood
without enhanced mRNA expression of Th2 cytokines and
suggest aberrant regulatory T-cell function in the immuno-
pathogenesis of AD in high-IgE Beagles.
This model was also used in experiments evaluating the
role of various routes of allergen exposure in relation to the
distribution of lesions and intensity of dermatitis (Marsella
et al., 2006a, b, c). In those studies it was found that pruritic
lesions could be induced by all routes, including a simple
oral challenge, and that, interestingly, the distribution of the
lesions was independent of the route used (for example,
epicutaneous, oral, or respiratory). Lesions were most severe
when an epicutaneous route was used. On the basis of
clinical scoring, the epicutaneous exposure showed the most
significant change since it induced the highest scores, but it
seems that, once allergic sensitization has occurred by the
epicutaneous route, a fixed pattern of reaction takes place
and the subsequent routes of exposure do not determine
the distribution of lesions.
Epidermal barrier dysfunction in canine AD
Impairment of the epidermal barrier has a primary role in
human AD. To evaluate whether barrier function is impaired
in this experimental model, transepidermal water loss (TEWL)
was measured in both sensitized atopic Beagles and normal
age-matched Beagles (Hightower et al., 2008). In those
experiments, it was found that TEWL is significantly increased
in the sensitized group, particularly in sites predisposed to the
development of AD (for example, antebrachial areas). Within
the sensitized group, the sites predisposed to the develop-
ment of AD consistently showed higher TEWL values than
areas not prone to AD. The increase was evident even when
no lesions were present and before any allergen exposure,
suggesting that it is a primary change. The increase in TEWL
is even larger after allergen exposure and development of
AD lesions in the atopic group, whereas the normal controls
did not experience significant changes after exposure to
D. farinae. Thus, exposure to mites in theabsence of an
allergic reaction does not alter TEWL values. These changes
are most evident in young dogs (for example, o2 years old)
and are minimal in older dogs (for example, 7 years old).
Therefore, it seems that this barrier dysfunction is a primary
change in young dogs genetically predisposed to the
development of AD and leads to an increased epicutaneous
penetration of the allergen. The findings in this canine study
are similar to reports in human medicine in which a
significant increase in TEWL was found when atopic infants
were compared with controls of the same age range during
the first year of life (Boralevi et al., 2008). Therefore, it seems
that, in both species, epicutaneous sensitization to allergens
occurs at a very early age in predisposed individuals because
of the deleterious effect of an impaired skin barrier. The fact
that the sites that are predisposed to the development of AD
have increased TEWL in the experimental model could also
lead to the speculation that those are the sites that in the very
early stages of the disease are more prone to allergen pene-
tration. Whether these differences are due to differences in
thickness or to specific abnormalities in the lipid composition
or filaggrin expression of those sites is unknown at this time, but
it warrants further investigation to better understand the mecha-
nisms determining the lesion distribution observed in AD.
Defects in the stratum corneum and at the junction with
the stratum granulosum were documented in high-IgE
Beagles, using transmission electron microscopy with ruthe-
nium tetroxide (Marsella et al., 2008). Whether these changes
may be linked to lipid abnormalities, as with the human
counterpart, is currently unknown. These abnormalities were
present before allergen exposure (nonlesional areas) and
were further exacerbated by allergen challenge. Changes
found in atopic dogs included a consistent widening of the
intercellular spaces, abnormal release of lamellar bodies, and
disorganization of lipid lamellae (Figure 4). Lamellar lipid
delamination, or ‘‘roll-up,’’ and widening of lipid lamellae
(cisternae) were common. Lamellar bodies were frequently
retained intracellularly in the stratum corneum of the atopic
Beagles, and the development of lesions triggered a marked
release of material morphologically resembling lamellar
bodies in the extracellular spaces between corneocytes.
Failure to form orderly organized lipid lamellae was also
commonly observed in the atopic group. It was also found
Figure 4. Clinical, histological and ultrastructural features of canine AD.
Transmission electron microscopy of the stratum corneum of a normal (a)
and an atopic dog (b and c). In the atopic samples widening of the
intercellular spaces and disorganization of lipid lamellae are evident in both
nonlesional (b) and lesional areas (c). Bar¼ 200nm.
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Canine Models of Atopic Dermatitis
that atopic Beagles had significantly less epidermal filaggrin
expression than did normal controls before any allergen
exposure and in the absence of clinical lesions (Marsella
et al., 2008). Morphologically, filaggrin staining appeared
different between groups: atopic samples had very fine
granules with faint staining, whereas normal samples showed
discrete granules with very intense staining. When both
groups were environmentally challenged with D. farinae, the
normal controls showed a significant decrease in filaggrin
expression, whereas the change in the atopic group was not
significant. Whether these dogs have any mutations in the
filaggrin gene is currently unknown. Given that filaggrin
expression can be modulated by cytokines (Howell et al.,
2007), it is conceivable that, even in the absence of any
mutation, the Th2-polarized response of this colony may be
responsible for this reduced expression. The morphological
difference in the keratohyalin granules in this experimental
model when compared with those in normal controls is
intriguing and warrants additional investigation.
One of the key questions at this point would be why
barrier-impaired AD skin mounts an insufficient innate
immune response but an exaggerated Th2 response. Also,
why is it that in dogs with impaired barrier function and
allergic sensitization, there is no progression to asthma or
allergic rhinitis? How can we best use these dogs to test new
therapeutic options aimed at restoration of the barrier
function of the skin and evaluate the implications of this
form of early intervention in altering the course of the disease
and in possibly preventing allergic sensitization?
Prevention of canine AD
We have shown that prenatal and postnatal administration of
probiotics in these dogs decreases allergic sensitization in
offspring (Marsella and Creary, 2007). When litters of puppies
from the same parents were exposed to probiotics during the
sensitization period, allergen-specific IgE synthesis could be
significantly decreased in the puppies to the point of falling
below levels considered clinically relevant compared to the
puppies that did not receive probiotics. Yet, once these
puppies were environmentally challenged with house dust
mites, they developed AD lesions, despite the absence of
allergen-specific IgE. However, the severity of the dermatitis
in the treated puppies was lower than that in control puppies,
which all developed high levels of allergen-specific IgE. Thus,
even in this model of extrinsic AD in which allergen-specific
IgE may function as an amplifying system for the develop-
ment of clinical disease, AD can develop in the presence of
reduced IgE. It is reasonable to speculate that the impairment
of the skin’s barrier function in this model is sufficient to
induce disease despite a modulation of the immune system
toward a less polarized Th2 response. Thus, it may be
productive to consider a multimodal approach to prevention
rather than focus on only one aspect of the disease at time.
Concluding remarks
Clearly, AD is proving to be one of the most complex and
intriguing diseases, and correcting one abnormality at a time
may lead to only partial success. It is possible that a
combination of early modulation of the immune system with
an early intervention to improve the barrier function of the skin
may lead to the most rewarding results. Using canine models,
it would be possible to carry out prospective studies of various
aspects of the disease, evaluating the role of different inter-
ventions and their possible combinations. It is hoped that
canine models can help unravel the mystery of AD and be a
useful tool for studies on pathogenesis as well as investigations
using experimental treatments, particularly in the screening
process, before lengthy clinical trials are considered.
CONFLICT OF INTEREST
The authors state no conflict of interest.
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	Canine Models Of Atopic Dermatitis: A Useful Tool With Untapped PotentialnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullIntroductionnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnull
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